Predicting toxicity after androgen deprivation:  skeletal adverse events Fred Saad MD FRCS
COI <ul><li>Consultant, research and honoraria  </li></ul><ul><ul><li>Novartis </li></ul></ul><ul><ul><li>Amgen </li></ul>...
Scope of the Problem
Incidence
Incidence > 30% will get ADT
Mortality
Mortality Almost all have bone mets
BMD changes after orchidectomy 0 0.2 0.4 0.6 0.8 1 1.2 1.4 2 4 6 8 10 12 14 Time After Orchidectomy (yr) BMD (g/cm  2  ) S...
Changes in BMD During GnRH Agonist Treatment Mittan et al.  J Clin Endocrinol Metab.  2002;87:3656 . 12-month data. Lumbar...
ADT Associated Bone Loss 1.   Kanis.  Osteoporosis . 1997:22; 2. Eastell et al.  J Bone Miner Res.  2002;17(suppl 1):S165;...
Prevalence of Osteoporosis at Baseline and Under ADT – Cross-sectional Data Overall prevalence of osteoporosis, osteopenia...
Relationship Between BMD  and Fracture Risk BMD T-score, SD units Fracture risk Osteoporosis Osteopenia 0 2 4 6 8 10 12 14...
ADT and Fractures  Shahinian VB, et al.  N Engl J Med.  2005;352:154-164. Years After Diagnosis Unadjusted Fracture-Free  ...
<ul><li>Hip fracture are a big problem: </li></ul><ul><li>1-year mortality for hip fracture in men is about 30-35%  </li><...
Higher Death Rate Observed at 36 Months in Patients With Vertebral Fracture at Study entry Smith, Saad et al. presented at...
Screening for bone loss in men:  Who is at risk?
FLAP: Four key risk factors  for fracture <ul><li>Family history of osteoporosis  </li></ul><ul><li>Low BMD </li></ul><ul>...
Indications for Bone Mineral Density (BMD) Testing <ul><li>Men aged 70 and older </li></ul><ul><li>Men under age 70 with c...
Factors independent of BMD that increase fracture risk in men <ul><li>Previous fragility fracture after age 40, especially...
Who should be treated? <ul><li>Men > 65 with T-score < -2.5 </li></ul><ul><li>Men > 50  </li></ul><ul><li>with previous fr...
FRAX
Treatment options
Pamidronate IV q 3months Lumbar Spine Total Hip P≤ 0.005 for each comparison Smith MR et al.  N Eng J Med.  2001;345:948. ...
Z oledronic Acid IV q 3 months Lumbar spine Total hip P <0.001 for each comparison Smith MR et al.  J Urol.  2003;169:2008...
Z oledronic Acid IV q 12 Months Lumbar spine Total hip P <0.005 for each comparison Michaelson MD et al.  J Clin Oncol.  2...
Alendronate PO weekly Lumbar spine Total hip P <0.04 for each comparison except  P =0.08 for total hip on placebo Greenspa...
Denosumab <ul><li>Investigational, fully human monoclonal antibody to RANK ligand </li></ul><ul><li>Rank ligand is essenti...
Denosumab Fracture Prevention Study R A N D O M I  Z E Denosumab q6 months for 3 years Current androgen deprivation therap...
Denosumab Increased  BMD at All Skeletal Sites 10 8 6 4 2 0 -2 -4 -6 0 1 3 6 12 24 36 Month Percent Change in BMD From Bas...
Denosumab Decreased  New Vertebral Fractures 0 2 4 6 New Vertebral  Fracture (%) Placebo Denosumab P =0.004 P =0.004 P =0....
Predicting bone metastases
Rising PSA in Non-Metastatic CRPC: PSA Levels Smith MR, et al.  J Clin Oncol  2005;23:2918-2925. 0.5 1 1.5 2.0 2.5 3.0 Pro...
Rising PSA in Non-Metastatic CRPC:  PSA Doubling Time (PSADT) Smith MR, et al.  J Clin Oncol  2005;23:2918-2925 . 0.5 1 1....
Denosumab to prevent metastases R A N D O M I  Z E Denosumab monthly Rising PSA despite ADT No bone metastases PSA >8  PSA...
Consequences of Bone Metastases Disease Bone  metastases Fracture Hypercalcaemia Surgery to bone Radiation  to bone SREs S...
Pathologic Fractures Negatively Affect Survival Saad F, et al.  Cancer.  2007;110(8):1860-1867. Hazard ratio 0 0.2 0.4 0.6...
Evaluating Risk and  Value of Bone Markers
In PC, %PABS Inversely Correlates with Survival Noguchi M, et al.  Br J Cancer . 2003;88:195-201. 0.8 0.6 0.4 0.2 0 Surviv...
# Bone Lesions and Risk for SRE > 3 Bone Lesions Versus ≤ 3 Bone Lesions Shirina N, et al. Presented at ASCO 2006. Poster ...
<ul><li>3 Bone Lesions Associated  With Shorter Time to SRE </li></ul>Baseline (n = 376) P  < .0001 < 3 0.0 0.1 0.2 0.3 0....
<ul><li>3 Bone Lesions  Associated With Shorter Survival </li></ul>Baseline (n = 376) P  < .0001 0 3 6 9 12 15 18 21 24 Ti...
SRE’s and risk of death <ul><li>Risk for dying within 1 year is greater among patients who have at least 1 SRE vs no SRE. ...
Bone Markers
Prognostic Implications of Bone Markers: Relative Risks in Prostate Cancer P  value <0.001 <0.001 <0.001 <0.001 <0.001 <0....
SRE vs BAP Level Cook et al.  Clin Cancer Res. 2006 Jun 3361-7.
Survival vs BAP Levels Cook et al.  Clin Cancer Res. 2006 Jun 1;12 :3361-7.
SRE vs Baseline NTX Level Cook et al.  Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3361-7.
Survival vs Baseline NTX Cook et al.  Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3361-7.
Normalization of NTX Levels vs Clinical Outcomes Among Patients With High NTX at Baseline 0 0.5 1.0 1.5 2.0 First SRE 0.61...
NTX Normalization Correlated With Improved Survival Versus Persistently Elevated NTX  Proportion deceased,  % patients Tim...
Survival Benefit by  Percentage Reduction From Baseline NTX High NTX, NTX >64 nmol/mmol creatinine Relative Risk of Death ...
Survival by Percentage Change From Baseline NTX in Placebo Group  *Calculated as ([Baseline NTX minus 3-month NTX] / basel...
A Phase 2 Study of Denosumab in Subjects With High NTx on IV Bisphosphonates BrCa PrCa MM Bone Met UNTx>50mmol despite ivB...
Patients With Reduced uNTx Levels Fizazi K, et al.  J Clin Oncol . 2009 Feb 23. [Epub ahead of print].
Treatment options
Zoledronic Acid and SREs Saad F, et al.  J Natl Cancer Inst . 2004;96:879-882 P  = .028 38 26 17 4 6 2 0 49 33 25 8 7 4 1 ...
Time to First Skeletal-Related Event <ul><ul><li>Median, days P  value </li></ul></ul><ul><li>ZOL 4 mg 488 .009 </li></ul>...
Cumulative expected Bone Complications (n) per 100 patients Months since randomization Placebo Zoledronic acid  4 mg P  = ...
Survival  Median, months   P  value ZOL 4 mg  18.2   .103 Placebo 15.6 ZOL 4 mg 214   162   113   56   10 Placebo 208   14...
Denosumab to prevent skeletal-related events R A N D O M I  Z E Denosumab monthly Castrate-resistant Bone metastases No pr...
Time to First and Subsequent On-Study SRE* (Multiple Event Analysis) Primary endpoint
Secondary endpoints
Overall Disease Progression Secondary endpoints
Summary and conclusions <ul><li>Men on ADT are at risk of bone loss and fractures </li></ul><ul><li>Risk adapted screening...
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NY Prostate Cancer Conference - F. Saad - Session 7: Predicting toxicity after androgen deprivation: skeletal adverse events

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  • Curatio PowerPoint Template 07/08/11 07:57
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  • Curatio PowerPoint Template 07/08/11 07:57 CORE
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  • Curatio PowerPoint Template 07/08/11 07:57 Adjusted for age and ADT duration OS balanced between treatment arms in overall population: 43 (6%) P vs 43 D (6%)
  • Curatio PowerPoint Template 07/08/11 07:57 [NOTE TO ART: lower case “X” to make “x-ray” in 3rd row. Delete table title and references in table. Insert the following at bottom of table: “Note: Entries in bold text are considered major risk factors.” Please make “Family history of osteoporotic fracture”, “Fragility fracture after age 40”, and “osteopenia evident on x-ray” boldface.] There are many risk factors for bone loss in men, including age ≥ 65 years, prostate cancer itself, and hypogonadism (including ADT-induced hypogonadism) 1,2 References: Brown JP, Josse RG; Scientific Advisory Council of the Osteoporosis Society of Canada. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ 2002;167(Suppl 10):S1-S34. Greenspan SL. Approach to the prostate cancer patient with bone disease. J Clin Endocrinol Metab 2008;93:2-7.
  • Curatio PowerPoint Template 07/08/11 07:57 Clinical practice guidelines (CPGs) on the diagnosis and management of bone loss identify four robust, independent predictors of osteoporotic fracture, listed on this slide. 1 Reference: Brown JP, Josse RG; Scientific Advisory Council of the Osteoporosis Society of Canada. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ 2002;167(Suppl 10): S1-S34.
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  • Curatio PowerPoint Template 07/08/11 07:57 DRAFT – For SCI Steering Committee Use Only Sept 2008 – Not for use in presentations Denosumab is an investigational, fully human monoclonal antibody that appears to bind (with high affinity) and inhibit the activity of human RANK (receptor activator of nuclear factor kappa B) ligand. 1 Amgen scientists have confirmed the essential role of RANK Ligand pathway in the formation, activation and survival of osteoclasts, the cells that are associated with bone resorption 1,3 . Since RANK Ligand is part of the TNF receptor superfamily, high specificity is demonstrated by the fact that denosumab does not bind to other TNF receptors. 2 Bekker PJ et al. J Bone Miner Res. 2004;19:1059-1066. Data on file, Amgen. Boyle WJ et al. Nature. 2003;423:337-342. Peterson HC et al. J Bone Miner Res . 2003;18(suppl 2):S166. Abstract SA393 and poster.
  • Curatio PowerPoint Template 07/08/11 07:57 From Smith (12018) No permission needed
  • Curatio PowerPoint Template 07/08/11 07:57 Figure 2 (pg 751) of Smith (12018) Permission needed Figure 2. Mean Percent Changes from Baseline Bone Mineral Density (BMD) Values during the Study Period, According to Skeletal Site and Study Group. Results are presented as least-squares means of the BMDs of the lumbar spine (Panel A), the total hip (Panel B), the femoral neck (Panel C), and the distal third of the radius (Panel D). All values shown were significantly higher in the denosumab group than in the placebo group (P≤0.001). The means were estimated with the use of analysis-of-covariance models adjusting for study group, stratification variables, baseline BMD value, densitometer type, and the interaction between baseline BMD value and densitometer type. The means are based on data for 734 patients in each of the two groups except for the distal third of the radius, for which data were available for 161 patients in the denosumab group and 148 patients in the placebo group. I bars indicate 95% confidence intervals.
  • Curatio PowerPoint Template 07/08/11 07:57 Figure 3 (pg 752) of Smith (12018) Permission needed Figure 3. Cumulative Incidence of New Vertebral Fracture at 12, 24, and 36 Months, According to Study Group. The relative risk for vertebral fracture among 679 patients in the denosumab group as compared with 673 patients in the placebo group was 0.15 at 12 months, 0.31 at 24 months, and 0.38 at 36 months.
  • Curatio PowerPoint Template 07/08/11 07:57 Elevation in serum PSA levels after surgery or radiation predates clinically or radiographically detectable metastatic disease. In a recent study, Smith et al. confirmed that baseline PSA predicts time to first bone metastasis and overall survival in patients with non-metastatic prostate cancer. 1 Different tertiles of PSA (&lt;7.7, 7.7 to 24, and &gt;24 ng/mL), as shown on the graph, were associated with different bone metastasis-free survival ( P &lt;0.001). Also, baseline PSA levels &gt; 10 ng/mL (RR,3.18;95% CI, 2.30 - 8.21; P &lt; 0.001) predicted shorter time to first bone metastasis. Reference: 1. Smith MR, Kabbinavar F, Saad F, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol 2005; 23:2918-2925.
  • Curatio PowerPoint Template 07/08/11 07:57 Rapid PSA doubling time (PSADT) predicts shorter time to first bone metastasis and shorter survival. 1 Different tertiles of PSADT, shown on graph, were associated with different bone metastasis-free survival. The independent predictive value of PSA velocity suggests that PSA kinetics may provide an effective strategy to identify men at high risk for bone metastases or death. As the optimal management of patients at high risk of metastatic disease remains uncertain, frequency of bone scans should be based on overall risk factors. Reference: 1. Smith MR, Kabbinavar F, Saad F, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol 2005; 23:2918-2925.
  • Curatio PowerPoint Template 07/08/11 07:57 Patients will remain on the trial and be treated for a maximum of five years or until disease progression, with letrozole as their adjuvant therapy beginning Day One. Patients will be randomized to one of two zoledronic acid treatment arms, receiving either upfront therapy with 4 mg, 15-minute infusions of zoledronic acid every 6 months beginning on Day One or a delayed start of the same bisphosphonate regime if a post-baseline bone mineral density decrease (–2.0 standard deviations) or a fracture are detected in the course of treatment. In the ZO-FAST study patients with menopausal induced by prior chemotherapy or LHRH agonist were allowed to enter in the study
  • Curatio PowerPoint Template 07/08/11 07:57 Bone metastases can result in debilitating skeletal-related events (SREs), which result in multiple negative consequences for cancer patients Increased morbidity and mortality Loss of autonomy and functional independence Increased healthcare costs
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  • Curatio PowerPoint Template 07/08/11 07:57 Zoledronic Acid (ZOMETA ® ) in Breast Cancer
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  • Curatio PowerPoint Template 07/08/11 07:57 In addition to impairing one’s quality of life, a person is at a significantly greater risk for dying within the first year of developing an SRE compared with patients who do not have an SRE. 1-year survival rates were 49.7% for patients who have no SRE versus 28.2% for those who had 1 or more SRE. References DePuy V, Anstrom KJ, Castel LD, et al. Effects of skeletal morbidities on longitudinal patient-reported outcomes and survival in patients with metastatic prostate cancer. Support Care Cancer. 2007;15:869-876.
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  • Curatio PowerPoint Template 07/08/11 07:57 Zoledronic Acid (ZOMETA ® ) in Breast Cancer
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  • Curatio PowerPoint Template 07/08/11 07:57 This is a phase 2 randomized, open-label, international trial of denosumab in patients with bone metastases from prostate, breast, or other cancer after receiving IV BPs. Background Patients eligible for inclusion in the study had: Histologically confirmed cancer ≥ 1 bone metastases uNTx levels &gt;50 nmol/L bone collagen equivalents (BCE)/mM creatinine despite IV BPs Patients were stratified by: Tumor type Screening uNTx levels (50 to ≥100 nmol/L BCE/mM creatinine) Patients were randomized: To continue receiving IV BPs (zoledronic acid or pamidronate) every 4 weeks or To receive subcutaneous (SC) denosumab 180 mg every 4 weeks or every 12 weeks Patients were on treatment for 25 weeks. During the 32-week follow-up period, patients had the option of entering a 2-year, ongoing extension study. Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol. 2009 Feb 23. [Epub ahead of print]. doi:10.1200/JCO.2008.19.2146.
  • Curatio PowerPoint Template 07/08/11 07:57 DRAFT – For SCI Steering Committee Use Only Sept 2008 – Not for use in presentations Among patients with bone metastases who had elevated levels of uNTx despite previous IV BP therapy, denosumab normalized uNTx more frequently than ongoing IV BP. 1 1. Fizazi K, et al. J Clin Oncol . 2008;26(suppl):176S. Abstract 3596 and poster.
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  • Curatio PowerPoint Template 07/08/11 07:57 Using a survival-adjusted event analysis that distinguishes between patients who go off study but remain at risk for bone complications versus patients who die and are no longer at risk, 1 Major et al. 2 demonstrated that zoledronic acid reduces the survival-adjusted cumulative incidence of radiation to bone and skeletal complications in patients with advanced prostate cancer. zoledronic acid significantly reduced the mean cumulative incidence of SREs by 35.3% ( P = 0.002) compared with placebo at 24 months. Similar analyses using data from each of the phase III trials of zoledronic acid have demonstrated that zoledronic acid significantly reduced the cumulative expected incidence of SREs compared with pamidronate in breast cancer patients ( P = 0.046) and compared with placebo in patients with prostate cancer ( P = 0.004) or lung cancer and other solid tumours ( P = 0 .010). 3 References: 1. Cook RJ, Lawless JF. Marginal analysis of recurrent events and a terminating event. Stat Med . 1997; 16: 911-924. 2. Major PP, Cook RJ, Chen B-L, Zheng M. Zoledronic acid reduces the survival-adjusted cumulative incidence of radiation to bone and skeletal complications in patients with advanced prostate cancer. ASCO:Prostate Cancer symposium . 2005; Abstract 282. 3. Major PP, Cook RJ, Chen B-L, Zheng M. Multiple event analysis of zoledronic acid trials in patients with cancer metastatic to bone. Proc Am Soc Clin Oncol . 2003;22:762. Abstract 3062.
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  • Curatio PowerPoint Template 07/08/11 07:57 Patients will remain on the trial and be treated for a maximum of five years or until disease progression, with letrozole as their adjuvant therapy beginning Day One. Patients will be randomized to one of two zoledronic acid treatment arms, receiving either upfront therapy with 4 mg, 15-minute infusions of zoledronic acid every 6 months beginning on Day One or a delayed start of the same bisphosphonate regime if a post-baseline bone mineral density decrease (–2.0 standard deviations) or a fracture are detected in the course of treatment. In the ZO-FAST study patients with menopausal induced by prior chemotherapy or LHRH agonist were allowed to enter in the study
  • Curatio PowerPoint Template 07/08/11 07:57 For the secondary endpoint of time to first and subsequent SRE (multiple event analysis) denosumab was also superior to zoledronic acid and reduced the risk of multiple events by 18% (rate ratio: 0.82; 95% CI: 0.71–0.94; P=0.004). Only events which were at least 21 days apart from each other were counted, matching a similar analysis reported for zoledronic acid in its registration trial (Saad et. al., JNCI 2004)
  • Curatio PowerPoint Template 07/08/11 07:57 Overall disease progression was also similar between groups (hazard ratio: 1.06; 95% CI: 0.95–1.18; P=0.30). Disease progression was determined by the sites per form shown below
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  • NY Prostate Cancer Conference - F. Saad - Session 7: Predicting toxicity after androgen deprivation: skeletal adverse events

    1. 1. Predicting toxicity after androgen deprivation: skeletal adverse events Fred Saad MD FRCS
    2. 2. COI <ul><li>Consultant, research and honoraria </li></ul><ul><ul><li>Novartis </li></ul></ul><ul><ul><li>Amgen </li></ul></ul><ul><ul><li>Sanofi Aventis </li></ul></ul><ul><ul><li>BMS </li></ul></ul><ul><ul><li>AstraZeneca </li></ul></ul><ul><ul><li>Millenium </li></ul></ul><ul><ul><li>Astellas </li></ul></ul><ul><ul><li>Janssen </li></ul></ul>
    3. 3. Scope of the Problem
    4. 4. Incidence
    5. 5. Incidence > 30% will get ADT
    6. 6. Mortality
    7. 7. Mortality Almost all have bone mets
    8. 8. BMD changes after orchidectomy 0 0.2 0.4 0.6 0.8 1 1.2 1.4 2 4 6 8 10 12 14 Time After Orchidectomy (yr) BMD (g/cm 2 ) Stepan et al. JCEM 1989;69:523 Normal Range early “rapid” bone loss 4-8% per yr
    9. 9. Changes in BMD During GnRH Agonist Treatment Mittan et al. J Clin Endocrinol Metab. 2002;87:3656 . 12-month data. Lumbar spine Total hip P < .001
    10. 10. ADT Associated Bone Loss 1. Kanis. Osteoporosis . 1997:22; 2. Eastell et al. J Bone Miner Res. 2002;17(suppl 1):S165; 3. Lee et al. J Clin Endocrinol Metab . 2002;87:329; 4. Maillefert et al. J Urol . 1999;161:1219; 5. Gnant. Breast Cancer Res Treat. 2002;76(suppl 1):S31. Abstract 12; 6. Shapiro et al. J Clin Oncol. 2001;19:3306. Normal men 1 Early menopausal women 1 Late menopausal women 1 AI therapy in PMW 2 Androgen deprivation therapy agonist 4 AI therapy plus GnRH agonist 5 Ovarian failure secondary to chemotherapy 6 Bone marrow transplant 3
    11. 11. Prevalence of Osteoporosis at Baseline and Under ADT – Cross-sectional Data Overall prevalence of osteoporosis, osteopenia, and normal BMD according to ADT duration. *Patients had not received ADT at time of BMD measurement. Percentage of patients Androgen deprivation therapy duration (years) Morote et al., UROLOGY 69: 500–504, 2007.
    12. 12. Relationship Between BMD and Fracture Risk BMD T-score, SD units Fracture risk Osteoporosis Osteopenia 0 2 4 6 8 10 12 14 16 18 -4 -3 -2 -1 0 1 2
    13. 13. ADT and Fractures Shahinian VB, et al. N Engl J Med. 2005;352:154-164. Years After Diagnosis Unadjusted Fracture-Free Survival (%) <ul><li>Over a 4-year period </li></ul><ul><li>19.4% fractures on ADT </li></ul><ul><li>12.6% fractures not on ADT </li></ul>2 3 4 5 6 7 8 9 10 1 0 100 90 80 70 60 50 40 30 20 10 No ADT (N=32,931) GnRH Agonist, 1- 4 doses (N = 3763) GnRH Agonist, 5 - 8 doses (N = 2171) GnRH Agonist,  9 doses (N = 5061) Orchiectomy (N = 3399)
    14. 14. <ul><li>Hip fracture are a big problem: </li></ul><ul><li>1-year mortality for hip fracture in men is about 30-35% </li></ul><ul><ul><li>Hip fracture affects life expectancy dramatically </li></ul></ul><ul><ul><li>Age 60-69 - 11.5 years decreased life expectancy </li></ul></ul><ul><ul><li>Age 70-79 - 5 years decreased life expectancy </li></ul></ul><ul><li>Even silent vertebral fractures are clinically important: </li></ul><ul><li>Prevalence in men is high (20%), though many are asymptomatic </li></ul><ul><ul><li>Predict subsequent clinical fracture in men </li></ul></ul><ul><ul><li>Predict mortality in men with a 10-year HR of 2.4 (95% CI 1.6-3.9) </li></ul></ul>Consequences of Fractures
    15. 15. Higher Death Rate Observed at 36 Months in Patients With Vertebral Fracture at Study entry Smith, Saad et al. presented at ECCO 2009
    16. 16. Screening for bone loss in men: Who is at risk?
    17. 17. FLAP: Four key risk factors for fracture <ul><li>Family history of osteoporosis </li></ul><ul><li>Low BMD </li></ul><ul><li>Age ≥ 65 years </li></ul><ul><li>Prior fragility fracture </li></ul>Brown JP, Josse RG. CMAJ 2002;167(Suppl 10):S1
    18. 18. Indications for Bone Mineral Density (BMD) Testing <ul><li>Men aged 70 and older </li></ul><ul><li>Men under age 70 with clinical risk factors for fracture. </li></ul><ul><li>Adults with a fragility fracture. </li></ul><ul><li>Adults with a disease or condition associated with low bone mass or bone loss </li></ul><ul><li>Adults taking medications associated with low bone mass or bone loss </li></ul>2007 ISCD Official Positions
    19. 19. Factors independent of BMD that increase fracture risk in men <ul><li>Previous fragility fracture after age 40, especially vertebral compression fracture </li></ul><ul><ul><li>(1 prior vertebral fracture increases risk for subsequent 4-fold) </li></ul></ul><ul><li>Systemic glucocorticoid therapy of >3 months </li></ul><ul><li>Advancing age, especially past 65 years (each decade past 50 ~ doubles fracture risk) </li></ul>Khan A, et al. CMAJ 2007
    20. 20. Who should be treated? <ul><li>Men > 65 with T-score < -2.5 </li></ul><ul><li>Men > 50 </li></ul><ul><li>with previous fragility fracture and T-score < -1.5 </li></ul><ul><li>Men of any age receiving glucocorticoid therapy for > 3 months with T-score < -1.5 </li></ul><ul><li>Men of any age with clinical hypogonadism </li></ul><ul><li>(from any cause) and T-score < -1.5 </li></ul>Khan A, et al. CMAJ 2007
    21. 21. FRAX
    22. 22. Treatment options
    23. 23. Pamidronate IV q 3months Lumbar Spine Total Hip P≤ 0.005 for each comparison Smith MR et al. N Eng J Med. 2001;345:948. Final 12-month data -5 -4 -3 -2 -1 0 1 2 BMD Percent Change No pamidronate Pamidronate
    24. 24. Z oledronic Acid IV q 3 months Lumbar spine Total hip P <0.001 for each comparison Smith MR et al. J Urol. 2003;169:2008. -4 -2 0 2 4 6 8 BMD Percent Change Placebo Zoledronic acid Final 12-month data
    25. 25. Z oledronic Acid IV q 12 Months Lumbar spine Total hip P <0.005 for each comparison Michaelson MD et al. J Clin Oncol. 2006;25:1038. -6 -4 -2 0 2 4 6 BMD Percent Change Placebo Zoledronic acid Final 12-month data
    26. 26. Alendronate PO weekly Lumbar spine Total hip P <0.04 for each comparison except P =0.08 for total hip on placebo Greenspan SL et al. Ann Intern Med. 2007;146:416. -3 -2 -1 0 1 2 3 4 5 BMD Percent Change Placebo Alendronate Final 12-month data
    27. 27. Denosumab <ul><li>Investigational, fully human monoclonal antibody to RANK ligand </li></ul><ul><li>Rank ligand is essential for osteoclast formation, function, and survival </li></ul><ul><li>Administration via subcutaneous (SC) injection </li></ul>
    28. 28. Denosumab Fracture Prevention Study R A N D O M I Z E Denosumab q6 months for 3 years Current androgen deprivation therapy for prostate cancer; Age >70 or T score <-1.0 (n=1,468) Placebo q6 months for 3 years Primary end point : change in lumbar spine BMD Key secondary end point : new vertebral fractures Smith MR et al. N Engl J Med. 2009;361:745.
    29. 29. Denosumab Increased BMD at All Skeletal Sites 10 8 6 4 2 0 -2 -4 -6 0 1 3 6 12 24 36 Month Percent Change in BMD From Baseline C. Femoral Neck Denosumab Placebo Difference at 24 mo, 3.9 percentage points 10 8 6 4 2 0 -2 -4 -6 0 1 3 6 12 24 36 Month Percent Change in BMD From Baseline 8 6 4 2 0 -2 -4 -6 0 1 3 6 12 24 36 Month Percent Change in BMD From Baseline A. Lumbar Spine Denosumab Placebo Difference at 24 mo, 6.7 percentage points Denosumab Placebo Difference at 24 mo, 4.8 percentage points B. Total Hip 8 6 4 2 0 -2 -4 -6 0 1 3 6 12 24 36 Month Percent Change in BMD From Baseline Denosumab Placebo Difference at 24 mo, 5.5 percentage points D. Distal Third of Radius Smith MR et al. N Engl J Med. 2009;361:745.
    30. 30. Denosumab Decreased New Vertebral Fractures 0 2 4 6 New Vertebral Fracture (%) Placebo Denosumab P =0.004 P =0.004 P =0.006 1.9 0.3 3.3 1.0 3.9 1.5 12 24 36 Month No. of Patients 13 2 22 7 26 10 Smith MR et al. N Engl J Med. 2009;361:745.
    31. 31. Predicting bone metastases
    32. 32. Rising PSA in Non-Metastatic CRPC: PSA Levels Smith MR, et al. J Clin Oncol 2005;23:2918-2925. 0.5 1 1.5 2.0 2.5 3.0 Proportion of patients with bone metastases or death Years since random assignment PSA >24.0 ng/mL PSA 7.7-24.0 ng/mL PSA <7.7 ng/mL 0.8 0.6 0.4 0.2 0 1.0
    33. 33. Rising PSA in Non-Metastatic CRPC: PSA Doubling Time (PSADT) Smith MR, et al. J Clin Oncol 2005;23:2918-2925 . 0.5 1 1.5 2.0 2.5 3.0 Years since random assignment PSADT <6.3 months PSADT 6.3-18.8 months PSADT >18.8 months 0.8 0.6 0.4 0.2 0 1.0 Proportion of patients with bone metastases or death
    34. 34. Denosumab to prevent metastases R A N D O M I Z E Denosumab monthly Rising PSA despite ADT No bone metastases PSA >8 PSADT <10 months (n~1500) Placebo monthly Primary End Point : Bone metastasis-free survival 4 Month delay in time to first metastases Smith et al. AUA 2011
    35. 35. Consequences of Bone Metastases Disease Bone metastases Fracture Hypercalcaemia Surgery to bone Radiation to bone SREs Spinal cord compression Loss of autonomy Consequences Significant morbidity Bone pain Decreased survival Increased healthcare costs and resources Ultimate consequence Reduced quality of life SREs = Skeletal-related events
    36. 36. Pathologic Fractures Negatively Affect Survival Saad F, et al. Cancer. 2007;110(8):1860-1867. Hazard ratio 0 0.2 0.4 0.6 0.8 1 1.2 1.4 1.6 1.8 2 De creased mortality Increased mortality .0 4 P value 29 % Risk increase 1.29 < .01 52 % 1.52 Prostate cancer Breast cancer
    37. 37. Evaluating Risk and Value of Bone Markers
    38. 38. In PC, %PABS Inversely Correlates with Survival Noguchi M, et al. Br J Cancer . 2003;88:195-201. 0.8 0.6 0.4 0.2 0 Survival Probability 0 10 20 30 40 50 60 70 80 90 Time (months) Less than 4.6% Greater than 4.6% Log rank p = 0.011 Less than 4.6% Greater than 4.6% 32 24 27 20 20 13 13 9 4 4 2 1 1.0
    39. 39. # Bone Lesions and Risk for SRE > 3 Bone Lesions Versus ≤ 3 Bone Lesions Shirina N, et al. Presented at ASCO 2006. Poster 8529. In favor of less lesions In favor of more lesions Lung cancer and other solid tumors 1.54 Hazard ratio 0 0.5 1 1.5 2 1.41 1.51 Prostate cancer Breast cancer
    40. 40. <ul><li>3 Bone Lesions Associated With Shorter Time to SRE </li></ul>Baseline (n = 376) P < .0001 < 3 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0 3 6 9 12 15 18 21 24 Time since randomization, months Proportion with SRE > 3
    41. 41. <ul><li>3 Bone Lesions Associated With Shorter Survival </li></ul>Baseline (n = 376) P < .0001 0 3 6 9 12 15 18 21 24 Time since randomization, months Proportion died 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 < 3 > 3
    42. 42. SRE’s and risk of death <ul><li>Risk for dying within 1 year is greater among patients who have at least 1 SRE vs no SRE. 1 </li></ul>1-year Survival Rate 49.7% (no SRE) 28.2% (≥1 SRE) P = 0.02 Matched-group Kaplan-Meier survival comparison of patients with no skeletal-related events versus one or more skeletal-related events DePuy V et al. Support Care Cancer. 2007;15:869-876. Days Probability of survival 0 90 180 270 360 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 No skeletal-related events One or more skeletal-related events
    43. 43. Bone Markers
    44. 44. Prognostic Implications of Bone Markers: Relative Risks in Prostate Cancer P value <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.003 <0.001 0.001 3.82 3.03 All SRE First SRE NTX ≥100 nmol/mmol creatinine BAP ≥146 IU/L NTX 50–100 nmol/mmol creatinine Brown J et al. J Natl Cancer Inst . 2005;97:59. Death 4.31 2.65 3.25 3.05 4.59 3.10 3.19 0.1 1 10 Relative Risk (vs lowest marker category) NTX, N-telopeptide of type I collagen; BAP, bone-specific alkaline phosphatase
    45. 45. SRE vs BAP Level Cook et al. Clin Cancer Res. 2006 Jun 3361-7.
    46. 46. Survival vs BAP Levels Cook et al. Clin Cancer Res. 2006 Jun 1;12 :3361-7.
    47. 47. SRE vs Baseline NTX Level Cook et al. Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3361-7.
    48. 48. Survival vs Baseline NTX Cook et al. Clin Cancer Res. 2006 Jun 1;12(11 Pt 1):3361-7.
    49. 49. Normalization of NTX Levels vs Clinical Outcomes Among Patients With High NTX at Baseline 0 0.5 1.0 1.5 2.0 First SRE 0.61 38% .0411 Death 0.41 59% < .0001 In favor of normalized NTX In favor of persistently elevated NTX Saad et al. Sem Urol Oncol 2010 Lipton et al. Cancer 2009 Risk reduction P value
    50. 50. NTX Normalization Correlated With Improved Survival Versus Persistently Elevated NTX Proportion deceased, % patients Time on study, months (starting at month 3) 100 80 60 40 20 0 3 9 12 15 18 21 24 27 6 RR = 0.410 P < .001 E  E E  N
    51. 51. Survival Benefit by Percentage Reduction From Baseline NTX High NTX, NTX >64 nmol/mmol creatinine Relative Risk of Death 0 0.25 0.50 0.75 1.00 1.25 Median baseline NTX (125 nmol/mmol creatinine) 5 15 25 Patients with NTX decrease ≤ corresponding x-axis value 35 45 65 85 95 – 3 17 37 57 77 97 NTX Decrease From Baseline* (%) (Decrease vs Baseline) No change NTX correlated with risk of death *Calculated as ([Baseline NTX minus 3-month NTX] / baseline NTX) × 100.  
    52. 52. Survival by Percentage Change From Baseline NTX in Placebo Group *Calculated as ([Baseline NTX minus 3-month NTX] / baseline NTX) × 100. All patients in this analysis had baseline NTX > 64 nmol/mmol creatinine. Relative Risk of Death 95 85 65 45 35 25 15 5 3.00 2.75 2.50 2.25 2.00 1.75 1.50 1.25 1.00 0.75 0.50 0.25 0.00 -222 -202 -182 -162 -142 -122 -102 -82 -62 -42 -22 -2 18 38 58 78 98 Median baseline NTX (145 nmol/mmol creatinine NTX Decrease From Baseline* (%) (Increase vs Baseline) (Decrease vs BL) No change NTX  correlated with  risk of death Saad F et al . Presented at: AUA Annual Meeting; May 2008; Orlando, FL. Abstract 519.
    53. 53. A Phase 2 Study of Denosumab in Subjects With High NTx on IV Bisphosphonates BrCa PrCa MM Bone Met UNTx>50mmol despite ivBp Denosumab 180 mg SC Q4W Denosumab 180 mg SC Q12W Bisphosphonate IV Q4W 25 weeks on treatment Optional 2-Year Extension/ Follow-up Up to 32 weeks off treatment Fizazi K, et al. J Clin Oncol . 2009 Feb 23. [Epub ahead of print].
    54. 54. Patients With Reduced uNTx Levels Fizazi K, et al. J Clin Oncol . 2009 Feb 23. [Epub ahead of print].
    55. 55. Treatment options
    56. 56. Zoledronic Acid and SREs Saad F, et al. J Natl Cancer Inst . 2004;96:879-882 P = .028 38 26 17 4 6 2 0 49 33 25 8 7 4 1 0 10 20 30 40 50 60 Any SRE Radiation to Bone Fractures Spinal Cord Compression Change in Antineoplastic Therapy Surgery to Bone HCM Zoledronic acid 4 mg (n = 214) Placebo (n = 208) Patients With SRE, %
    57. 57. Time to First Skeletal-Related Event <ul><ul><li>Median, days P value </li></ul></ul><ul><li>ZOL 4 mg 488 .009 </li></ul><ul><li>Placebo 321 </li></ul>Saad F, et al. J Natl Cancer Inst . 2004;96:879-882 Percentage without event 167 days 0 20 40 60 80 100 0 120 240 360 480 600 720 Time after start of study drug, days
    58. 58. Cumulative expected Bone Complications (n) per 100 patients Months since randomization Placebo Zoledronic acid 4 mg P = 0.002 20 40 60 100 120 80 0 3 6 9 12 15 21 18 24 27 Risk of Developing a Bone Complication Reduced by 35% Saad F, et al. J Natl Cancer Inst . 2004;96:879-882
    59. 59. Survival Median, months P value ZOL 4 mg 18.2 .103 Placebo 15.6 ZOL 4 mg 214 162 113 56 10 Placebo 208 148 94 40 5 Saad F, et al. J Natl Cancer Inst . 2004;96:879-882
    60. 60. Denosumab to prevent skeletal-related events R A N D O M I Z E Denosumab monthly Castrate-resistant Bone metastases No prior bisphosphonate (n~1800) Zoledronic acid monthly Primary End Point : Skeletal-related events
    61. 61. Time to First and Subsequent On-Study SRE* (Multiple Event Analysis) Primary endpoint
    62. 62. Secondary endpoints
    63. 63. Overall Disease Progression Secondary endpoints
    64. 64. Summary and conclusions <ul><li>Men on ADT are at risk of bone loss and fractures </li></ul><ul><li>Risk adapted screening and treatment approach is possible </li></ul><ul><li>Men with metastatic CRPC are at high risk of SRE’s </li></ul><ul><li>Two active agents available </li></ul><ul><li>Bone markers may useful in the clinic in predicting outcome and guiding therapy in the future </li></ul><ul><li>Therapy to delay bone metastases may soon be available </li></ul>

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